The international patent applications WO 03/029232 and WO 2007/144005 disclose the compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine including various manufacturing routes. In the remainder of this document, 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts thereof are respectively referred to as Compound I and Compound I XX when reference to the XX salt is desired.
Compound I is an antagonist on the 5-HT3, 5-HT7 and 5-HT1D receptors, an agonist on the 5-HT1A receptor and a partial agonist on the 5-HT1B receptor and an inhibitor of the serotonin transporter. Additionally, Compound I has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound [J. Med. Chem., 54, 3206-3221, 2011; Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur. Neuropshycopharmacol., 21(suppl 4), S407-408, 2011; Int. J. Psychiatry Clin Pract. 5, 47, 2012].
Compound I has in clinical trials shown to be a safe and efficacious treatment for depression. A paper reporting the results from a proof-of-concept study to evaluate the efficacy and tolerability of the compound in patients with major depressive disorder (MDD) authored by Alvares et at was made available on-line by Int. J. Neuropsychopharm. 18 Jul. 2011. The results from this six weeks, randomised, placebo-controlled study with approximately 100 patients in each arm show that Compound I separates significantly from placebo in the treatment of depressive and anxious symptoms in patients with MDD. It is also reported that no clinically relevant changes were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. Results from a long-term study also show that Compound I is effective in preventing relapse in patients suffering from MDD [Eur. Neuropsychopharmacol. 21(suppl 3), S396-397, 2011].
WO 2007/144005 discloses a manufacturing process in which the compounds
are mixed in the presence of a base and a palladium catalyst consisting of a palladium source and a phosphine ligand. The palladium catalysts catalyses the formation of the C—N bond as disclosed in U.S. Pat. No. 5,573,460. In the above process, the piperazine may optionally be protected at one of the nitrogens. This process gives the desired compound in a high yield and with a relatively high purity. Nevertheless, impurities are formed which subsequently have to be removed. It is particularly difficult to remove impurities which like compound I contain secondary amine, i.e. a piperazine moiety. Such compounds tend to have similar solubility properties, e.g. including pH-dependent solubility properties, and are thus difficult to separate from Compound I using methods that take advantage of differences in solubility, e.g. crystallisation. WO 2010/094285 discloses a purification process which effectively removes such impurities, e.g. 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-4-(2-piperazin-1-yl-phenyl)-piperazine which is formed when both nitrogens in the piperazine group form a C—N bond. The purification process comprises precipitating an isopropanol solvate of Compound I, HBr.
The present invention provides a new manufacturing route which eliminates or reduces the above mentioned difficult-to-remove impurities.